Musculoskeletal disorders are the leading cause of disability in the U.S. and account for more than half of all chronic conditions in people older tha 50 years. Many drugs used to treat musculoskeletal conditions have preventable life threatening side effects. An important target for interventions to decrease such severe adverse events is drug-drug interactions. Particularly important are drug interactions mediated by CYP3A, the cytochrome P-450 (CYP) member that is involved in the metabolism of more than 60% of all drugs. This proposal will define the risk of CYP3A mediated drug-drug interactions and their role as underlying mechanisms explaining preventable adverse events for drugs commonly used to treat patients with musculoskeletal conditions. Using state of the art pharmacoepidemiologic techniques and large databases of TennCare and Medicare enrollees, the studies will assemble cohorts receiving selected CYP3A substrate drugs with great potential for toxicity: (1) the opioids oxycodone and fentanyl and (2) colchicine users and define the risk of clinically important outcomes associated with concurrent therapy with CYP3A inhibitors. Better understanding of these risks will lead practitioners to avoid concomitant use of interacting drugs that lead to clinically significant toxicity. The applicant, Dr. Chung, has a strong background in clinical and epidemiological research and is committed to an academic career in rheumatology and pharmacoepidemiology. She obtained a Master of Public Health degree at Vanderbilt and completed additional training in clinical pharmacology, funded by a T-32 grant. Concurrently, she completed rheumatology fellowship under the American Board of Internal Medicine research track. Dr. Chung's career goal is to become an independent investigator and this plan aims to strengthen her knowledge in pharmacoepidemiology, advanced biostatistics, and clinical pharmacology. These are necessary skills for her transition to become competitive for R01 funding. Vanderbilt University offers her an exceptional environment to develop a successful independent career. The leaders in the Department of Medicine and the Divisions of Rheumatology and Pharmacoepidemiology fully support her plans. Furthermore, Dr. Chung's mentors, Drs. Ray and Stein, are internationally recognized, have a successful track record of mentoring independent investigators, are well-funded, and have committed the time and resources required to train her and foster her career. The K-23 award will allow Dr. Chung to build on her strengths and get the protected time and resources to acquire the skills needed for an independent career in academic rheumatology and pharmacoepidemiology.

Public Health Relevance

Many frequently prescribed drugs to treat patients with musculoskeletal conditions have narrow therapeutic indices and have metabolic pathways susceptible to drug interactions. Further characterization of the risk of clinically important toxicities associated with drug interactions involving medications frequently used with musculoskeletal diseases is important. Defining the adverse consequences of these preventable adverse drug interactions will lead practitioners to avoid concomitant use of interacting drugs that lead to significant toxicity.